The c-MYC (MYC) gene is a key molecular regulator of cellular growth and differentiation. Myc protein is a transcription factor that activates expression of many genes via binding of consensus sequences (Enhancer Box sequences (E-boxes)) and recruitment of histone acetyltransferases (HATs). Myc can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, Myc inhibits expression of Miz-1 target genes. In addition, Myc has a direct role in the control of DNA replication (Dominguez-Sola et al. Nature 448 (7152): 445-51).
Various mitogenic signaling pathways, including Wnt, Shh and EGF (via the MAPK/ERK pathway), have been demonstrated to activate Myc. Myc's role in modifying the expression of its target genes has been shown to cause numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but Myc also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation and stem cell self-renewal. Myc is a strong proto-oncogene and it its upregulation has been described in many types of cancers. Myc overexpression stimulates gene amplification (Denis et al. Oncogene 6 (8): 1453-7), via a mechanism believed to involve DNA over-replication.
At least because of the MYC oncogene's propensity to increase cell proliferation when specifically mutated or overexpressed, MYC is an attractive target for inhibitory oncotherapeutics, including small molecule and nucleic acid inhibitors of MYC.
Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35 nucleotides have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Patent Application Nos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents. Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220).
Provided herein are improved nucleic acid agents that target MYC. In particular, those targeting MYC have been specifically exemplified.